Basic ethers of aralkyl phenols and salts thereof



Unimd States Patent BASIC ETHERS OF ARALKYL PHENOLS AND SALTS THEREOF Stephen B. Binkley, Elmhurst, 11]., and Lee C. Cheney, Fayetteville, N. Y., assignors to Bristol Laboratories Inc., Syracuse, N. Y., a corporation of New York No Drawing. ApplicationAugust 30, 1950,

Serial No. 182,412

9 Claims. (Cl. 260-3096) This application is a continuation-in-part of our copending applications Serial No. 760,694, .filed July 12, 1947, now abandoned, Serial No. 37,304, filed July 6, 1948, now abandoned, and Serial No. 128,028, filed November 17, 1949, nowabandoned.

This invention relates to new basic ethers of aralkyl phenols having the general formula:

wherein X designates a member of the group :consisting of benzene, naphthalene, and quinoline; R1 andfR are members of the group consisting of hydrogen, alkyl, hydroxy, cyclohex'yl, alkoxy, amino, dialkylamino, nitro, halogen and cycloalkyl; m and n are inte gers from 1 to 4; R2 is a member of the class consisting of alkylene, substituted alkylene, and unsaturated alkylene; "R3 -repre; sents a straight or branched alkylene chain containing from 1 to 6 carbon atoms, inclusive; Z designates a member of the class consisting 'of 'alkylamino, cycloalkylamino, dialkylamino,-1 pyrrolidyl, l piperidyl, 4-morpholinyl, 1-(2-meth'ylpiperid'yl), thiomorpholinyl, substituted piperazinyl and the following radicals:

NCHa :NH

and Y designates a member of thegroup consisting of benzene, pyridine, thiophene, and -furan.

This invention alsoincludes the-acidaddition .salts of 2,703,324 Patented Mar. 1 1955 Ice or mist. The more active compounds of the invention are indicated for therapeutic use in humans for allergic conditions (asthma, urticaria, histamine cephalgia, anaphylactic shock) and in smooth muscle spasm (biliary spasm, dysmenorrhea).

The compounds of this invention are prepared by reacting a secondary or tertiary amino alkyl halide with a metal salt, preferably an alkali metal salt of an aralkylphenol. Alternatively, the compounds may be prepared by reacting a primary or secondary amine with an aralkylphenoxyalkyl halide. Also, an alkyl aralkylphenoxyacetate may be caused to react with .a 1,2 diamine or a 1,3-diamine to give an aralkylphenoxymethylimidazoline or an aralkylphenoxymethyltetrahydropyrimidine.

The quaternary salts of this invention may be prepared by causing substituted aralkylphenoxyalkyl amines to :react with alkyl halides, ,aralkyl halides,.alkyl sulfates or alkyl p-toluenesulfonates. Alternatively, the quaternary saltsmay be-prepared bycausing an aralkylphenoxyalkyl halide to react with atertiary amine.

The salts, such as the citrates of the aforementioned basic ethers, may be made .by reacting the metal salt of the aralkylphenol with an aminoalkyl halide, following which an aqueous solution of the acid to be used,

- for example, citric acid, is added to the reaction mixture.

The resulting mixtnreis then cooled and the precipitated salt is collected by filtration. The advantage of this process is that isolation of the intermediate basic ether is not necessary, thus allowing a saving of equipment,

* time and chemicals.

The following examples are given to illust of this invention'without limitingit thereto.

All temperatures mentioned in each of the following A solution 30f. ;1-38,grams of 4 -ethoxyphenol in 200 cc. of toluene is added dropwise to a stirred suspension of 24 grams of sodiu'muhydride in 200 cc. .of toluene. A vigorous evolution of hydrogen occurs, accompanied by the generation of heat. At the end of the addition, a light green suspension ofthe sodium phenolate is present. To this suspension, which still contains some unreacted ratethe scope sodium hydride, are now.- added dropwise 140 grams of benzyl chloride. No heat effect is observed during .the addition, but when the mixture is heated to boiling, an evolution of heat is. noticed. The reaction mixture is refluxed, withgstirring, for five hours, then cooled and hydrolyzed with ice and hydrochloric acid. The toluene maleate, acetate, citrate, oxalate, succinate, benzoate, V

topossess localanesthetic and antihistaminic activity,

and arealso useful as antifungal agents.

The compounds of the-invention-arerpotent-antlhistamine agents are revealed 'by'their "ability toalleviate'the severe b'renchiocons'trictio in "guinea" 'pigs' induced ""by layer is separated, washed with Water, then washed with saturatedsodium bicarbonate "solution, then "extracted several times with Claisens alkali. Acidification of the alkaline solution "with hydrochloric acid liberates the phenolic product, which is removed by-extractionwith histamine administration; 'fhe 'co'rn'pounds are extremely active in preventinganaphylacticyshock. in sensitized guinea pigs. In vitro experiments with gnmea plg lleal muscle suspended in Tyrodis solution, prove that these compounds are remarkably active in preventing smooth muscle spasm induced by suchagents as histamine or acetyl-choline chloride.

The compounds may be administered to humans as the hydrochloride or other salts orthe free bases.

They may be given orally, parenterally, rectally, or as a vapor ether. The combined ether extracts are dried, the solvent evaporated and the residuedistilled in vacuo. There is obtained akforer-unof recovered.4=ethoxyphenol, followed by 95.8 grams of 2-benz yl-4-ethoxyphenol, B. P.

;',-Anqalternate.-method for working up the product gives equally good results. The toluene solution obtained on hydrolysis 'is evaporated to dryness, and the residue dissolved in approximately-four times its volume of'Claisens alkali. After repeated extraction with petroleum ether to remove the neutral material, the alkaline solution is EXAMPLE 2 4-methoxy-2-benzylphenol %ii%;.? Found EXAMPLE 3 4-cycl0hexyl-2-benzylphenol B. P. l88-196/2 mm., M. P. 87.5-89.0".

Analysis:

1 %3.-&;.% Found EXAMPLE 4 4-tertiar'y butyl-Z-benzylphenol (came (am- 3 B. P. 151/1.5 mm.l62/2.5 mm.

Analysis:

EXAMPLE 5 2-(alpha-methylbenzyl)phenol CH: Q

B. P. 122-126/1.5 mm.

Analysis:

3 Found EXAMPLE 6 2-(4'-isopr0pylbenzyl) phenol cm-Q-omcm B. P. 134137/1 mm.

Analysis:

bfifisll Found EXAMPLE 7 2-(2,3'-dimethoxybenzyl) phenol OCH: OCH:

B. P. 148-154/1 mm., M. P. 1255-1271).

Analysis:

iifellff Found EXAMPLE 8 2-(4-meth0xybenzyl) phenol CH2--OCHI B. P.154-157/1 mm., M. P. 80.0-81.5".

Analysis:

so iihlzli Found 0 78.5 78.3 H s. s 6.6

EXAMPLE 9 2-(2',4-dichlorobenzyDphenol c1 CH3-C1 55 B. P. 142147/1 mm.

Analysis:

(1. 7o C ii iioO h Found (6 EXAMPLE 10 2-(5'-chlor0-2'-ihenyl)phenol (Jane EXAMPLE r1 2- (4 -fluorobenz "01 A solution of 132 grams (-1-.41 moles') of phenol in 50 ml. of toluene is added slowly to a stirred suspension of 33.8 grams"('1.4'1 moles) of sodium hydride in 750 ml. of toluene. To the resulting suspension of sodium'phenoxide, stirred and maintained at gentle reflux, is added dropwise 205 grams (1.4 1 moles) of"4-fluorobenzylcl1loride. The reaction mixture iszrefluxedfor l'2hours. Following hydrolysis with 'dilute hydrochloric acid, the toluene is removed by steam distillati'on. The residualoil is separated from the water, taken up in *Ske'llysolve D and shaken with 300 ml. ofClai'sens-alkali. Acidification f the aqueous layer liberates thephenolic material, which is extracted into ether. Distillation of the ether extracts gives 117 grams (41% yield) of 2-(4'-fluorobenzyl)- phenol.

Analysis:

Calcd. for 0 131111 0 F Found oxide is caused to react with benzyl chloride. to give 4-.fluoro-2-benzylphenol, B. P. 117-123=/1 mn1. (41% yield).

Analysis .Calod. {or

O'HHHOF I Found EXAMPLE l3 4-z'odo-2- banzylphenol on v In the manner described (l1),sodium 4-iodophenoxide is caused to reactwith benzyl. chloride to g1 ve 4-1odo- 2-benzylphenol, B. P. l63]67/1 mm. (44% yleld).

EXAMPLE 14 4-a'imethylamino-Zbenzylph-ehdl One hundred grams (0.26811nole) .-of 4-dimethylaminophenol sulfate is shakenwith 500 ml. of saturatedxsodium bicarbonate and 200 ml. of chloroform "until-complete solution is attained. The chloroform Ilayeris drawn 101T and the aqueous layer extracted 5 twice with fresh -gchloroform. The combinedextracts are dried, an equal volurne of toluene added, and. the chloroform distilled 011. The resulting toluene solution of 4-dimethylaminophenol is added gradually to a suspension of 12 grams (0.5 mole) of sodium hydride in 300 ml. of toluene. After one hours reflux, 62 grams (0.5 mole). of benzyl chloride is added dropwise to the suspension of sodium 4-dimethylaminophenoxide. The reaction mixture is refluxed for 1.5 hours, then hydrolyzed with water. The toluene layer is filtered, dried, stripped and distilled in vacuo. The entire distillate boiling between 120 and 210 :at 2-3 mm. is retained (69 grams). The distillate is taken up in 2.00 ml. of Claisens alkali and extracted twice with Skellysolve D. Hydrochloric acid is added to the aqueous layer until the pH falls to 8; the mixture is, then extracted thoroughly with ether. The ether extracts are combined, dried, stripped and the residual oil distilled to give 16.4 grams of 4-dimethylamino-2-benzylphenol, 'B P. l65l80/1 min, n 1.6030.

EXAMPLE 15 2- (3'-thenyl phenol CH2- I \S In the manner described in (11), sodium phenoxide is caused to react with 3-thenyl bromide to give 2-(3- thenyl.)phenol, B. P. l24-l30/1 mm. I

EXAMPLE 16 2- (2'-furfuryl) phenol In the manner described vin (11)., sodium phenoxide is caused to react with Z-furfuryl bromide to give 2-:(2- furfuryDphenol.

EXAMPLE l7 7-benzyl-8-hydroxyquinoline A solution of grams (0.69 mole) of S-hydroxyquinoline in 250 ml. of toluene is added slowly to a stirred suspension of 16.5 grams (0.69 mole) of sodium hydride in 750 ml. of toluene. The reaction mixture .is refluxed for thirty minutes, and then 78 grams (0.69 mole) of benzyl chloride is added dropwise over a period of five hours. After refluxing overnight, the .reaction mixture is hydrolyzed with dilute hydrochloricacid. Sodium bicarbonate isadded until the pH rises to 8. The

toluene layer is then removed and the solvent stripped under reduced pressure. The residue is taken up in 400 ml. of Claisens alkali and extracted twice with Skellysolve D. Careful adjustment of the pH of the aqueous layer to 7 with hydrochloric acid causes a semi-solid material to separate, which is extracted with ether -containing a little chloroform. The extracts are combined, dried and stripped. Distillation of the residue gives 93 grams (58% yield) of 7-benzyl-8-hydroxyquinoline,

EXAMPLE 18 Z-(Z-pyridylmethyl) phenol To a stirred suspension of 55.8 grams (1.47 moles) of lithium hydride in 1.3 liters of dry ether is added dropwise a solution of 201 grams (1.48 moles) of Z-methoxybenzaldehyde (prepared from salicylaldehyde according to the method given in Organic Syntheses, Col. vol. II, p. 619) in 800 ml. of dry ether. After fifteen hours stirring at room temperature, the reaction mixture is cautiously hydrolyzed with dilute sulfuric acid, having first decomposed the excess lithium aluminum hydride with absolute alcohol. The ether layer is removed, dried and stripped. Distillation gives 181 grams (88% yield) of 2-methoxybenzyl alcohol, B. P. 101-103/ 3 mm.

A solution of 179 grams (1.29 moles) of Z-methoxybenzyl alcohol in 300 ml. of dry ether is saturated with dry hydrogen chloride at After standing overnight at 5, the ether is evaporated in a current of air; the residual oil washed twice with Water, once with saturated sodium bicarbonate and again with water. This oil is dissolved in 300 m1. of alcohol and added to a solution of 80.5 grams (1.64 moles) of sodium cyanide in 125 ml. of water over a period of 40 minutes. The reaction mixture is allowed to stand at room temperature for 30 minutes, then refluxed for four hours. The cooled mixture is filtered, and as much alcohol as possible evaporated on the steam bath. The remaining material is extracted thoroughly with ether; the ether extracts dried, stripped and distilled to give 2-methoxyphenylacetonitrile, B. P. 125-135/9 mm. The product solidifies, and on recrystallization from cyclohexane gives 82.8 grams of nitrile melting at 69.070.5 (44% yield).

To a stirred suspension of 21.9 grams (0.56 mole) of sodium amide in 500 ml. of toluene, under a nitrogen atmosphere, is added a solution of the aforementioned 2-methoxyphenylacetonitrile in toluene over a period of 30 minutes. After stirring for 30 minutes more, a solution of 68 grams (0.6 mole) of Z-chloropyridine in 200 ml. of toluene is added dropwise thereto. The reaction mixture is gradually heated to reflux and maintained there for three hours. Hydrolysis is effected by the careful addition of 50 ml. of alcohol, followed by 250 ml. of water. The toluene is removed by steam distillation.

The supernatant oil is removed from the residue and distilled twice; there is obtained 19.0 grams of alpha-(2- pyridyl)-2-methoxyphenylacetonitrile, B. P. 154-1 57/ 1 mm., M. P. 67.6-71.5.

A solution of 19.0 grams (0.29 mole) of potassium hydroxide and the above alpha-(2-pyridyl)-2-methoxyphenylacetonitrile in triethylene glycol is refluxed for 14 hours, cooled and poured into water. The solution is extracted with ether and the extracts discarded. The water layer is boiled to remove residual ether, then acidified to pH 7 with acetic acid. The white precipitate is taken into ether, the ether extracts dried and evaporated to dryness. Recrystallization of the residue from isopropyl alcohol gives 6.5 grams (38% yield) of 2-(2'- pyridylmethyl)phenol, M. P. 95.097.0.

Analysis: Calculated for C12H11ON Calculated Found EXAMPLE 19 2-(2'-thenyl)phen0l To a stirred solution of 256 grams (2.72 moles) of phenol in 1280 ml. of toluene heated to boiling under reflux was added portionwise 62.0 grams (2.7 gram atoms) of sodium. After all of the sodium was dissolved, at solution of 358.6 grams (2.72 moles) of 2-theny1 chloride in 500 ml. of toluene was added dropwise during 1.5 hours. The mixture was refluxed overnight, then cooled, treated with sufiicient water to dissolve inorganic salts and rendered strongly acid (pH 2) with hydrochloric acid. The toluene layer was extracted with portions of 15% sodium hydroxide solution until a sample of extract gave no precipitate when acidified. The combined dark colored alkaline extracts (ca. 1 liter) were washed once with ether to remove residual neutral material, then cooled and acidified to pH 2 with 6 N hydrochloric acid. The liberated phenol was extracted with 1.5 liters of ether, and the extract was washed with sodium bicarbonate solution and dried over sodium sulfate. Following removal of the solvent from the filtered solution, the product distilled at 135-150 at less than 1 mm.; weight, 154.1 grams.

In order to eliminate the para isomer through its insoluble barium salt, the product was added to a boiling solution of 200 grams (1.17 moles) of barium hydroxide octahydrate. The mixture was boiled ten minutes, cooled to 10-15 and filtered. The filtrate was made strongly acid (pH 2) with hydrochloric acid and the product was extracted with ether. The ether extract was washed with sodium bicarbonate solution, dried over sodium sulfate and distilled to obtain 118 grams of pure 2-(2-thenyl)- phenol, B. P. -132 at less than 1 mm.

EXAMPLE 20 Z-benzylphenyl beta-dimethylaminoethyl ether Ca CHI Sodium methylate is made by dropping 11.7 grams of sodium strips into 199 ml. of absolute methanol in a 1-liter three-necked flask. 93.9 grams of o-benzyl-phenol are dissolved in 200 ml. of dry toluene and added to the sodium methylate solution. The solution is distilled until the boiling point of toluene is reached. At the end of the distillation, enough toluene is added to restore the original volume of solvent.

One hundred nine and five tenths grams of dimethylaminoethyl chloride hydrochloride and 200 ml. of toluene are placed in a 1-liter Erlenmeyer flask, cooled in an ice bath, and decomposed with 167.5 grams of 20% sodium hydroxide solution. The toluene and Water layers are separated, and the water layer is extracted again with 50 m1. of toluene. The toluene layers are combined, washed with saturated salt solution, and dried over anhydrous potassium carbonate.

The dried dimethylaminoethyl chloride solution is poured into the toluene solution of the sodium salt of obenzylphenol, heated to reflux, and refluxed 16 hours. After refluxing, enough water is added to the mixture to dissolve the precipitated solid. The layers are separated, and toluene layer is further washed with water until the water extract is just slightly alkaline. The toluene solution is then made acid with 6 N hydrochloric acid and extracted with water until no cloudiness is produced when the extract is made alkaline. The acidic aqueous extract is washed with ether, then made alkaline with 20% sodium hydroxide solution, and extracted into ether. The ether solution is washed several times with water, then with saturated salt solution, and is dried over anhydrous potassium carbonate. The dried solution is filtered and distilled. The product distills at 143.5 1 mm.; 69.7 grams of pale yellow oil are recovered.

Fifty-seven and one tenth grams of the free base are dissolved in ether and precipitated with dry HCl. 66.0 grams of crude hydrochloride are recovered. The hydrochloride is dissolved in 130 ml. of reagent acetone by boiling, filtered hot, and allowed to cool. The crystalline material obtained on cooling is filtered, washed with a little acetone, washed with ether, and dried in vacuo. Forty-four and eight tenths grams, M. P. 119.5 to 121, are recovered from the first crop of crystals. Ethyl acetate may also be used as the solvent for recrystallization.

The following salts may be prepared by reacting the freebase with the corresponding acid in a suitable sol- 2-benzylphenyl beta-diethylaminoethyl ether Three-and two tenths grams of sodium are dissolved in 54 ml. of absolute methanol. Twenty-five and four tenths grams of o-benzylphenol are dissolved in 165 ml. of dry toluene and added to the solution of sodium methylate. The resulting solution is distilled until all the methanol is removed and the temperature is up to the boiling point of toluene.

Thirty-five grams of diethylaminoethyi chloride hydrochloride and 100 ml. of toluene are placed in a 500- ml. Erlenmeyer flask. The cooled mixture is made alkaline with 45 grams of 20% sodium hydroxide solution. When all the solid is dissolved, the mixture is filtered by suction. The toluene layer is separated from the water layer. The water is further extracted with 50 ml. of toluene. The toluene extracts are combined, washed with a little saturated salt solution, and dried over an hydrous'potassium carbonate.

The dried and filtered diethylaminoethyl' chloride solution is added to the hot toluene solution of the sodium salt of o-benzylphenol. The mixture is stirred and heated to reflux. It is refluxed about 12 hours.

One hundred fifty ml. of water are added to the mixture to dissolve the precipitated solid and the layers are separated.

The toluene layer is washed with 27 grams of 20% sodium hydroxide and then with 200 ml. of water in 50 ml. portions. It is finally washed with saturated salt solution and dried over anhydrous potassium carbonate.

The dried and filtered solution is distilled at reduced pressure. Thirty grams of a pale yellow oil are recovered; B. P. l60-l64/ 1 mm.

Thirty grams of the base are dissolved-in ether and the hydrochloride is precipitated by piping in dry hydrogen chloride. Thirty-three and three tenths grams, M. P. 155-l57, of the crude hydrochloride are recovered. It is dissolved in 110 ml. of hot isopropanol which, on cooling, deposits small white crystals. Thirty and eight tenths grams are recovered which are again dissolved in 84 ml. isopropanol and recrystallized. Yield, 29.9 grams, M. P. 158-159.

Analysis:

Caled. for CnHzsONCl mm o 71. 5 71. 4 H; s. 2 s. 12

Fifty-nine and seven tenths grams (0.26 mole) of metallic sodium is dissolved in 102 m1. of absolute methanol. When the sodium is dissolved, the alcohol is distilled off. To the methoxide is added 47.9 grams (0.26 mole) of o-benzylphenol dissolved in about 300 ml. of toluene.

Meanwhile, 96.0 grams (0.52 mole) of piperidylethyl chloride hydrochloride is covered with 250 m1. of toluene and decomposed with a solution of 23 grams of sodium hydroxide pellets dissolved in 46 ml. of water. The aqueous layer is withdrawn and the toluene layer'washed twice with a saturated solution of sodium chloride. lt is dried over potassium carbonate while shaking. It is then filtered and added to the solution of the methoxide and o-benzylphenol and themixture refluxed and stirred for 20 hours.

The tan turbin solution is transferred to a separatory funnel and washed twice with water. I't'is then extracted with four 50-ml. portions of 3-molar hydrochloric acid. The combinedacid extracts are washed'with a small portion of ether and made strongly basic with a 20% solution of sodium hydroxide. This is extracted with 500 ml. of ether in several portions. The combined ether extracts are washed twice with a saturated salt solution and dried over potassium carbonate.

The dried etheral solution is filtered and the ether removed by distillation. The residue is distilled at diminished pressure collecting two fractions:

Fraction one: 164-182/1 mm, wt. 33.9 grams Fraction two: 180-183/1 mm., wt. 37.5 grams Both fractions are clear yellow liquids.

Both fractions are converted to the hydrochloride by piping dry hydrogen chloride into an etheral solution of the base:

Fraction one: wt. 37.7 grams, M. P. 1 35-13 9 Fraction two: wt. 41.7 grams, M. P. -139 The combined fractions are recrystallized in acetone; Wt. 47.6 g., M. P. 135-141".

EXAMPLE 23 Z-benzylphenyl beta-(4- morpholinyl)-ethyl ether Five and seventy-five hundredths (0.25 mole) grams of metallic sodium is dissolved in 98 ml. (17 ml. of methyl alcohol, absolute, per gram of sodium) of methyl alcohol. absolute. When the sodium is dissolved the alcohol is distilled off. To the methoxide is added 46.06 grams (0.25 mole) of o-benzylphenol dissolved in about 300 ml. of toluene.

Meanwhile, 93.04 grams (0.5 mole) of beta-4-morpholinylethyl chloride hydrochloride is decomposed by dissolving it in a solution of 22 grams of sodium hydroxide pelletsdis'solved in 44 ml; of water covered with 200 ml. of toluene. The aqueous fraction is withdrawn, the toluene fraction washed twice with a' saturated salt solution and dried over potassium carbonate with shaking. Itis then filtered and. added to the solution of: the methoxide and o-benzylphenolr- I The combined solutions are refluxed and stirredfor 16-hours.

The tan solutionis transferred-do a separatory funnel Analysis:

1 Calcd. for CNHZO2NC1 I Found EXAMPLE 24 Z-benzylphenyl beta-dimethylaminoisopropyl ether (N0. 1) and Z-benzylplzenol beta-dimethylaminopropyl ether Six and nine tenths grams of sodium are dissolved in 117 ml. of absolute methanol in a 3-necked 500 ml. flask. Fifty-five and two tenths grams of solid o-benzylphenol are added to the sodium methylate solution, dissolved, and the resulting solution subjected to reduced pressure distillation. The methanol comes off, leaving the solid, white sodium salt of o-benzylphenol. One hundred eighty ml. of dry toluene are added and the distillation is continued at atmospheric pressure till the boiling point of toluene is reached. Enough additional toluene is added to bring the volume up to what is lost in the distillation.

Fifty-nine and five tenths grams, B. P. 118-120" of freshly distilled dimethylamino chloropropane, obtained by the action of thionyl chloride on l-dimethylaminopropanol-2, is added to the warm toluene solution of the sodium salt of o-benzyl-phenol and the resulting solution is heated to reflux. Refiuxing is continued for six hours.

Two hundred ml. of water are added, the precipitated solid dissolves in the water, and the water and organic layers are separated. The toluene layer is washed with 60 ml., 20% sodium hydrochloride, then several times with water and finally with saturated salt solution. It is then made acid with 1:1 hydrochloric acid and extracted with water until there is no cloudiness when the extract is made alkaline. The acid extract is washed with ether, then it is made alkaline with 50% sodium hydroxide solution. The base, a pale yellow oil, separated to the top. The water layer is drawn off and extracted with a 100 ml. and 50 ml. portion of ether. The ether solutions are combined with the oil, a little more ether is added and the solution is dried over anhydrous potassium carbonate. Before drying, the ether solution is washed with three SO-ml. portions of water and one of saturated salt solution.

The dried solution is distilled at reduced pressure. Two cuts are made.

Cut No. 1: 27.5 grams, B. P. 148-152/1 mm. Cut No. 2: 19.4 grams, B. P. 152.5-157/1 mm.

They are both clear colorless oils.

The hydrochloride is made of the material by dissolving the base in ether and precipitating the hydrochloride with dry hydrogen chloride. The crude hydrochloride is dissolved in reagent acetone and recrystallized. In attempting to crystallize the material again from acetone,

12 it is found to be insoluble. Ten and four tenths grams, M. P. 170-171.5 are recovered.

Analysis: Hydrochloride No. 1:

Calculated Found The acetone mother liquors are concentrated by distilling off the acetone. It is then dissolved in water, made alkaline with 20% sodium hydroxide solution, and ex tracted into ether. The ether solution is dried over anhydrous potassium carbonate. The dried ether solution is treated with dry HCl and the hydrochloride precipitates. This material after being thoroughly washed with ether and dried under vacuum is dissolved in hot ethyl acetate and crystallized. After two crystallizations from ethyl acetate, 23 grams, M. P. 7982 are recovered.

Analysis: Hydrochloride No. 2:

Calculated Found The proof of structure of Z-benzylphenyl beta-dimethylaminopropyl ether is accomplished by the following unequivocal synthesis:

(2-benzyl)phen0xy acetone.-Following the general procedure of Hurd and Perletz, J. A. C. S. 68, 38-40 (1946), for the preparation of phenoxy-acetone, 184 grams (1 mole) of o-benzylphenol, 34 grams of potassium carbonate and 200 ml. of dry acetone were placed in a 2 l., three-necked flask and stirred and refluxed for fifteen minutes. To this stirred mixture was added in four equal portions a mixture of 138 grams (1.5 moles) of chloroacetone, 3 grams of potassium iodide and ml. of acetone which had stood for 24 hours: 34 grams of potassium carbonate and 50 ml. of acetone were added after each addition of halide. After 28 hours of refluxing and stirring, the mixture was filtered through a sintered glass funnel, and the filtrate was concentrated. Attempted distillation of the residue gave considerable decomposition. The residue was dissolved in ether, washed with 10% sodium hydroxide until basic, charcoaled, filtered and stripped. After standing for several days, the residual dark oil set up. Successive recrystallizations from cyclohexane, ethanol and isopropanol gave 52 grams (21.5%) of material of M. P. 6466. The low yield may be partially ascribed to the decomposition during distillation.

Analysis Calcd. for 015 Found C 80. U 80. 1 H 6. 71 G. 68

Analysis:

Calcd. for CroHnNO 2 Found Beta-(Z-benzyl)phenoxyispropylamine.-A solution of 30 grams (0.12 mole) of (2-benzyl)phenoxy acetone oxune in 450 ml. of dry ether was added to a stirred suspension of 4.5 grams (0.12 mole) of lithium' a'luminum hydride in 300 ml. of dry ether 'over-a -30minuteperiod. The mixture was stirred for 1% hours at room temperature, and the excess hydride was destroyed by cautious addition "of ice. Four hundred mL-Qfsaturated potassium sodium tartrate :solution were added with stirring; the ether layer was separated, and the aqueous layer extracted twice with ether. The-combined etherlayer .and extracts were washed twice with saturated sodium chloride solution, dried over anhydrouspotassium carbonate and distilled under reduced pressure. Distillation was erratic, but'a good fraction was obtained at '175.6/ 1.5 mm.

The main fractions were combined, dissolved in ether and treated with hydrogen chloride. 'The precipitate was recrystallized once from isopropanol, M. P. 146147. The yield of hydrochloride was 11.5 grams (35%).

Analysis:

Caled. for

Z-benzylp'henyl betmdimethy'laminopropyl eth.er.Nine and one tenth grams (0.033 :mole) of ;beta-.(2-benzyl) phenoxyisopropylamine hydrochloride Was neutralized with 10% sodium hydroxide andtheibase "taken up'into ether. Washing with water and .then saturated saltsolution, drying over anhydrous potassium carbonate and stripping, yielded 8.0 grams of amine. This was dimethylated "by the-procedure of OrganicSyntheses, 25, :89, and the product taken up in ether, washed with water and dried over potassium carbonate. not isolated.

Dihydrogen citrate-To the ethereal solution of 2- benzylphenyl beta-dimethylaminopropyl ether :was added a solution of 7.7 grams (0.04 mole) of anhydrous citric acid in 12 ml. of water. After standing overnight, the mixture was filtered, and the-white solid was recrystallized twice from ethanol. Rosettes of needles, M. P. 119-121 (dec.). The yield was 8.2 grams (54%).

Analysis:

0 l d.f cisli ilN l Found Methiodide.-Four grams of Z-benzylphenyl beta- The amine was dimethylaminopropyl ether dihydrogen citrate was treated 7 of material, M. P. 154.5155.5'.

Analysis Calcd ior CmHnINO Found 2-benzylp'henyl-beta-dimethylaminopropyl ether .dihydrogen citrate.-A concentrated'aqueous solution 'of' the hydrochloride of the low melting (M. P. 82) isomer from the reaction between 2-benzylpheno1 and 'l-dimethylamino-2 chloropropane "(hydrochloride No. 2) was shaken'with 50 ml. of 10% sodium hydroxide, and the free base extracted into ether. The'combinedether extracts were dried over'anhydrous -K2CO3, filtered, and diluted to 170 ml. with dry ether. Eighty-five mlaof this solution was allowed to stand overnight with a-solution'of 2.64 grams of anhydrous citric acid in 4 ml. of water. The suspension was cooled, and the crystalline compound was collected 'by filtration and recrystallized from alcohol. Weight, 4.2 grams, M. 'P. -1215 (dec.).

Analysis:

0 1 d.i CSEBIN B Found gave 154.5-156 Equations .for structural proof:

0 v K260: I I

OH ClCH OH: O-CH2CCH3 Acetone NHQO H.HC1

pyridine-ethanol e@ LiA1H4 OCHzCHNHa O-CH2.0 CH:

other I Ha N OH H C O OH HOBO V Methiodide /CH: OGHaCHN\ Dihydrogen citrate EXAMPLE Z-benzylphenyl dimethylaminopropyl ether dihydrogen citrate H3 CH7 An aqueous solution of 7.0 grams of 2-benzylpheuyl dimethylaminopropyl ether hydrochloride, the preparation of which is described in Example 24, and which is designated hydrochloride No. 2 therein, is made basic with 50 ml. of 10% sodium hydroxide and the liberated basic ether extracted into ether. The ether extracts are dried over anhydrous potassium carbonate and filtered. To one-half of the resulting solution is added 2.64 grams of anhydrous citric acid and the mixture allowed to stand overnight. The crude salt is collected by filtration and recrystallized from 95% ethanol to give 2-benzylphenyl dimethylaminopropyl ether dihydrogen citrate, M. P. l20.0121.5.

Analysis:

Gal (1. i CuH aiCgT Found EXAMPLE 26 4-benzylphenyl betadimethylaminoethyl ether C H: -CH2 -O-CH7CH2N\ Two and eight tenths grams of sodium are cut into strips and dissolved in 48 ml. of absolute methanol in a 500 ml. three-necked flask. Twenty-two and three tenths grams of 4-benzylphenol are added and dissolved. The methanol is distilled off at reduced pressure leaving the white sodium salt of p-benzylphenol.

Thirty-four and five tenths grams of dimethylaminoethylchloride hydrochloride are put with 70 ml. of toluene into a 500 ml. Erlenmeyer flask, cooled and decomposed with 52 grams of 20% sodium hydroxide. The toluene and water layers are separated, and the water layer is extracted with ml. more of toluene. The toluene layers are combined, washed with saturated salt solution, and dried over anhydrous potassium carbonate.

One hundred twenty ml. of dry toluene are added to the sodium salt of p-benzylphenol and, with stirring, the mixture is heated and solvent distilled off until the boiling point of toluene is reached. One hundred additional ml. of toluene are added. The mixture is allowed to cool below the reflux temperature, and to it, with stirring, is added the dried solution of dimethylaminoethyl chloride. The mixture is then heated to reflux and refluxed for 24 hours.

The solution is treated with enough water to dissolve the precipitated solid and the layers are separated. The toluene layer is washed with more water. The toluene layer is made acid with 1:1 hydrochloric acid and the layers separated. It is extracted further with water until the extract does not become cloudy on being made alkaline. The acid extract is washed with ether and is then made basic with 50% sodium hydroxide solution. The product separates to the top as a yellow oil. The oil is separated and the water layer is further extracted with two lOO-ml. portions of ether. The ether and oil layers are combined, washed with five SO-ml. portions of water, a little saturated salt solution, and dried Over anhydrous potassium carbonate.

The solution is distilled at reduced pressure. Nineteen and eight tenths grams of product, boiling point l52l53/l mm., are recovered.

Nineteen and eight tenths grams of the base are dissolved in ether and the hydrochloride is precipitated as a fine white powder with dry hydrogen chloride. This material is recrystallized from isopropanol. It crystalliggd is?2 long flat crystals. Weight, 21.6 grams, M. P. 1 -1 16 Analysis:

0 1 (1.! Oul l iol bl Found EXAMPLE 27 Bela-dimethylaminoethyl 2-(2' thenyl)-phenyl ether OCHzCH2-N C a CH:

A stirred solution of 118.7 grams of o-(2-thenyl)-ocresol in 660 ml. of toluene was distilled until all traces of water and 130 ml. of toluene had been removed from the system. To this dry solution was then added a solution of sodium methoxide freshly prepared from 14.6 grams (0.635 gram atom) of sodium and 225 ml. of absolute methanol. In order to remove the methanol, distillation was continued until constant boiling point of 109 was observed and 640 ml. of distillate was collected. A solution of 0.95 mole of beta-dimethylaminoethyl chloride in 250 ml. of dry toluene was then added to the cooled suspension of the phenate and the stirred mixture was refluxed for 18 hours. The cooled suspension of the phenate was extracted with 395 ml. of 3 N hydrochloric acid in six portions and the combined acid extracts were washed with ether, made strongly basic with 10% sodium hydroxide solution and extracted with 700 ml. of ether in three portions. After drying over potassium carbonate, the extract was freed of solvent and the product was collected at 158-165/1 mm. with the major portion distilling at 159-160, weight, 129.6 g.

Analysis:

Calcd. for for the base Found CisHioNOS The hydrochloride salt was prepared by dissolving 64.2 grams of the base in dry ether and saturating the solution with dry hydrogen chloride. The solid which precipitated melted at 129-l30 after recrystallization from acetone; wt., 531 grams.

EXAMPLE 28 4-eth0xy-2-benzylphenyl beta-dimethylamino-ezhyl ether solution dried by shaking over anhydrous potassium carbonate for four hours.

A solution of 83.2 grams of 4-ethoxy-2-benzylphenol in 250 cc. of toluene is added dropwise to a stirred suspension of 8.7 grams of sodium hydride in 250 cc. of toluene. An exothermic reaction occurs with the evolution of hydrogen. The mixture is refluxed for two hours to insure complete reaction. To the resulting mixture, maintained at gentle reflux, is added dropwise the above described solution of beta-dimethylaminoethyl chloride. Sodium chloride begins to precipitate out almost immediutely. After 17 hours refluxing, the reaction mixture is hydrolyzed with water and the toluene layer separated,

8,708,824 washed wgh claiso 's alkaliggfiod and strf'ipfedfi Dizs- EXAMPLE 32 ti ation o e resi ue gives grams -c oxy- 7 ig i vg betadimethylaminoethyl ether 4 cyclohexyl 2 benzylpheerl zlhefa dzmethylammoethyl A solution of 34.3 grams of this basic ether in 250 cc. 5 a of ether is cooled to ice-bath temperature and saturated with dry hydrogen chloride. After standing overnight OH; in a cold room, the solid material is collected by filtration; there are obtained 24.4 grams, M. P. 130-134. Recrys- Y P tallizgltionffriomhisoprzoganol pfitroleun ether gilvels white d 0H: cryst s 0 -et oxyenzylp enyl eta-dimet yamino- B. a ethyl ether hydrochloride, M. P. 136.0-137.0. w 5 3 190 H mm gydmchlonde P 152 Analysis: 7 Analysis;

v c 1 d. r cufizfioal bl Found cg fiifi l Found 0-- 67.9 67.7 H 7.8 7.0 g-- 3;: 5:: In a manner similar to that described above there are I EXAMPLE 33 obtained a number of other basic ethers from various substituted phenols and beta-dimethylaminoethyl chloride. 44871147) yl- -benzylpheltltyl betq-dtmethylammoethyl EXAMPLE 29 2-benzyl-4-tolyl beta-dimethylaminoethyl ether Q CHI 30 GK v on o-omam-N I cm 7 a B. P. 168-174/3 mm. Hydrochloride: M. P. 12o.s as 1 Hydmchlmide 128.0. v, Analysis: a

' C1d.f

Found clrzafloN bl Found V o 72 s 72.6 n 7 7 H v r 8.7 8.8

EXAMPLE so EXAMPLE 4-chloro-2-benzylphenyl betardimethylaminoethyl ether 2-(4 'methoxybenzyl)ph223,1etafdlmethylammoethy l a on; on.

c1- o-crr=orn-N o-omcm-n OH: \CH| B. 1 172-17671 mm. Hydrochloride: M. P. 173.s 1;. P 149-152'/1 mmy w hl ri e: M. P. 1210- 17 p Analysis: Analysis:

' i c d.

oofi fih h Found Gg aiQzl l bl Found 0-- i V 62.6 62.7 0 67.2 67.0 H 6.5 6.5 H y 7.5 7.5

EXAMPLE 31 EXAMPLE 35 4-methoxy-2-benzylphenyl beta-dimethylaminoethyl ether '-chlorobenzyl)phenyl beta-dimethylaminoethyl ether CHiour-@421 CH; cm CHsO- Oe-CHgCH N 0-CH1CHr-N on. ,v on; l132P6 17417 7/'1 mm. Hydrochloride: M. P. 1310- 3P8 179'-185/3 mm. Hydrochloride: M. P. 152.0-

Ahalysis: Analysis:

am. i cufi oz l bl Found V I l cga fi l ah Found 6 #2 7.3- 0 103 a is 7.6 11 7 I gt-g g3 19 20 EXAMPLE 36 EXAMPLE 40 2-(4-isopropylbenzyl)phenlyl beta-dimethylaminoethyl 2 (2' chlorobenzyhphengzl beta dimethylaminoethyl et er et er CH: 5 C1 G OH: on em @o-cmcm-n O--CH:CHr-N C \CH:

CHa B. P. 155167/1 mm. Hydrochloride: M. P. 139.5- B. P. 1s1-1s2/1 mm. Hydrochloride: M. P. 144.0- 1425 145.5. Analysis:

Analysis:

Calcd. for Found Og%l;%1fll Found O11H21ONCh C 62.6 62.5 O' 71.9 72.1 H F 8.5 8.5

EXAMPLE 37 2 (3' chloroben li h h n i b eia dimeth laminoeth l 2-(2',3'-dimethoxybenzyl)phenyl beta-dimethylaminozy i y y ethyl ether Cl OCH: OCH; WC;

' /CH: Q-CHJCHPN\ O-GHzCHx-N C CH! \CH: B. B. P. 146-152/1 mm. Hydrochloride: M. P. 120.0-

Analysis: 121.5

Analysis: 83. 363? M C alcd. for Found 4 C17H21ONG12 0. 72.3 72.2 H M o 6 .a 62.3 H 6.5 6.6 EXAMPLE 38 Z-cinnamylphenyl beta-dimethylaminoethyl ether EXAMPLE 42 Q 2 ehloro 6 benzylphenyl beta dimethylamz'noethyl 0H=0H=0H ether CHI CH2 O-CHaCHx-N CH:

CH: OCH:CH2N/ 11356P5. 137141/1 mm. Hydrochloride: M. P. 154.()- 1 I Analyslsi B. P. 160/1-173.3 mm. Nitrate: M. P. 93.0-96.0".

0 M i alysis:

f 0131240130] Found 081 d f C 01' Found 0- 71'8 7L9 CiIHnOANaCl H 7.6 7.8

.1-3 EXAMPLE 39 2 (5 chloro 2' therzylgplfnyl beta-dimethylamino- XA 43 t e y et er 4 chloro 2 (4' chlorobenzyl)phenyl beta dimethylaminoethyl ether 0H s 01 (am-Q01 I OH CH Cl- 0CH10HN\ OHl CH: 1136613 149-150/1 mm- Hydrochloride: M. P. 103.0- 1 5213 177182/1 mm. Hydrochloride: M. P. 150.0-

Anaiysis: A nalysis:

C l d. CuH JOI C hB Found cgfi z o l h Found C. 64.2 64.3 0-- H 5.8 5. 7 H 2.2 2.3

unease GHQ B. R 200-20772 Hydrochloride: M. P. 1183.5- 1855 Analysis:

2-(2',4"-dichlorobenzyl)phenyl beta-dimethylaminoethyl ether CHs B. P. 149152/1 mm. Hydrochloride: M. P. 139.5- 141.0.

Analysis:

shaken vigorously in a sealed. bottle for 22 EXAMPLE 4a 4,6 dichlbi'o' 2 lienzylbhenyl' Beta" dim'ethylaminoethyl ether Analysis:

- 0alcd.tor fCnHaoONCli mm 0 j (satev 56.4 H- 6.6 6.6-

EXAMPLE 49 Dimethyl. Z-benzylphenoxyacetamidine hydrochloride N (C Hah-HCI To a vigorously stirred and refluxingsuspension of 108 grams and 2-benzylphenol and 79 tassium carbonate in cc. of methyl ethyl ketone is added dropwise over a period of two hours a solution of 49 grams of chloroacetonitrile in 45 cc. of methyl ethyl ketone. This solution of chloroacetonitrile has stood overnight in the dark in the presence of 1.5 grams of sodium iodide. The reaction mixture is refluxed one hour after the addition of the nitrile solution has been completed, then 130 cc. of solvent stripped. The residue is taken up in dilute hydrochloric acid and ether and the. insoluble material removed by' filtration. The filtrate is extracted several times with ether; the combined ether extracts washed in turn with 10% potassium hydroxide solution, saturated sodium bisulfite solution, dried and stripped. Distillation of the residue in. vacuo gives 108.3 grams of 2-benzylphenoxyacetonitrile, B. P. 137- 143 1 mm.

Dry hydrogen chloride is passed into an ice-cold solution of grams of the above nitrile in 100 cc. of chloroform and 23 grams of absolute ethanol until the gain in weight amounts to 18.2 grams. Dilution of the solution with 700 cc. of ether causes the precipitation of a white crystalline material, which is collected and dried: 102.6 grams, M. P. 108.5111.0. The precipitation of ethyl 2-benz ylphenoxyacetimidate hydrochloride as awhite crystalline mass, is collected and dried: 102 grams, P. 108.5-11l.0.

Dimethylamine is passed into 60 grams of absolute ethanol until the gain in weight equals 5.9 grams. To this solution is" added all phenoxyacetimidate grams of anhydrous pohydrochloride. The. mixture is 72 hours. At the end. of this time, a suspension of white crystals was present.

curred, and the insoluble. material was collected by filtration: 20.6 grams M. P. 181-208. The crude dimethyl 2-benzylphenoxyacetamidine hydrochloride was recrystallized from 95% ethanol; M. P. 218-226'.

Analysis:

Calcd. for C11H2oONCla Calcd. for

at once 30.5 grams of ethyl 2-benzyl Ether was added until no further precipitation oc- 23 EXAMPLE 50 2-(o-benzylphenoxy)methylimidazoline N-CH| A solution of 92 grams (0.5 mole) of o-benzylphenol in 200 cc. of benzene is added dropwise to a stirred suspension of 12 grams (0.5 mole) of sodium hydride in 100 cc. of benzene. After the addition had been completed, the reaction mixture was refluxed for 30 minutes. To the hot solution was added dropwise 61 grams (0.5 mole) of ethyl chloroacetate, whereupon sodium chloride began to precipitate. The mixture was refluxed 20 hours, then cooled and hydrolyzed with ice and hydrochloric acid. The benzene layer was separated, washed with dilute sodium hydroxide solution, dried and stripped. Distillation of the residue gave 108 grams (80% yield) of ethyl o-benzylphenoxyacetate, B. P. 177-180/ 3 mm.

Analysis:

Caled. for

CuHuOa Found Calcd. for

EXAMPLE 51 Z-benzylphenyl beta-isopropylaminoethyl ether hydrochloride Thirty-four grams (0.58 mole) of isopropylamine is added slowly to a solution of 56.3 grams (0.193 mole) of 2-benzylphenyl beta-bromoethyl ether, which may be prepared by reacting sodium 2-benzylphenoxide with ethylene dibromide, in 80 ml. of dioxane. The container is sealed and the mixture heated on the steam bath overnight. The solvent and excess isopropylamine are distilled under reduced pressure. The residue is treated with an excess of sodium hydroxide and the liberated basic ether taken up in ether. On shaking the ether extract with 6 N hydrochloric acid, the hydrochloride precipitates. Recrystallization from water gives 47.7 grams (81% yield) of 2-benzylphenyl beta-isopropylaminoethyl ether hydrochloride, M. P- 174-175.

Analysis:

Caled. for

CHHHONCI Fmmd 24 EXAMPLE 5:

Z-benzylphenyl beta-methylaminoethyl ether hydrochloride O-GHaCHs-NH-OHz-HCI In the manner described in Example 51, but using methylamine in place of isopropyl amine, there is obtained 2-benzy1phenyl beta-methylaminoethyl ether hydrochloride, M. P. 178.5179.5.

EXAMPLE 53 Z-benzylphenyl gamma-dimethylamino-beta,betadimethylpropyl ether CH CH: O-GHz-JJ-C Hr-N H: CH;

A suspension of 37.2 grams (0.2 mole) of gammadimethylamino-beta,beta-dimethylpropyl chloride hydrochloride in 50 ml. of toluene is stirred with 25 ml. of 56% potassium hydroxide until the hydrochloride is completely decomposed. The toluene layer is decanted and the aqueous slurry stirred with three 50-ml. portions of fresh toluene. The combined toluene decantates are dried by shaking over anhydrous potassium carbonate. A solution of 36.8 grams (0.2 mole) of 2-benzylphenol in 200 ml. of toluene is added dropwise to a stirred suspension of 4.8 grams (0.2 mole) of sodium hydride in ml. of toluene. The mixtureis refluxed for an hour to insure complete conversion of the 2-benzylphenol to its sodium salt. To this clear hot solution is added dropwise the above-mentioned toluene solution of gammadimethylamino-beta,beta-dimethylpropyl chloride. The

. reaction mixture is then stirred and refluxed overnight.

Analysis:

Calcd. for CzoHnON mm EXAMPLE 54 Z-benzylphenyl gamma-1-piperidyl-beta,betadimethylpropyl ether In the manner described in Example 53, by using 2- benzylphenol and gamma-l-piperidyl-heta,beta-dimethylpropyl chloride hydrochloride, there is obtained 2-benzylphenyl gamma-l-piperidyl-beta,beta-dimethylpropyl ether (92% yield), B. P. 171174 1 mm., n 1.5433.

Calcd. for O iaHu N EXAMPLE ss Menzylphenyl' bera-eyciohexyiaminaeihyi alter" In the manner described in Example 53, by using 2- benzylphenol and beta=cyclohexylaminoethyl ehlori'de by dro'chloride, there is obtained 2-benzylphenyl beta-cycle: hexylaminoethyl ether (35% yield), B. P. 165=171l1 Hydrochloride: M. P; I82.0-'-183.5 (recrystallized from isopropyl alcohol).

An al'ys'is:

Calcd. for

CnHuONCl Fmmd EXAMPLE 56 I fi-benzylplienyl gamma-di r'rhutylamimprbpylether I In the manner described in Example 53', by using 2- b'enzylplrenol and gamma-di-n-butylaminopropyl chloride hydrochloride, there is obtained Z-benzylphenyl gammadi-n-butylar'ninopropyl ether (98% yield), B. P. 174'- 1767I mm. Hydrochloride: M. P. 86.0-89.0 (recrystallized from ethyl acetate).

. Analysis-z CHaCHaCHaCHI Calcd. for

CnHauONOl mm Mmylphanfl gainmii l pipridylpropyl ether 1 OKs-C Analysis:

Caled. for CMHQIONC] mm 0.. 13.0 12.9 H a2 as EXAMPLE 5:; 2-benzylphenyl garfii'rza-1-(2-methylpiperidyl)propyl ether --o--omcmem-N Inthe manner described in Example 57, by using 2- benzylphenyl gammwbromopropyl ether and Z-methylpiperidine, there is obtained 2-benzylphenyl gamma-1-(2- ma pip ynpropvl e her .6%.. eld), ,.194- 197/1 mm. Hydrochloride: 149.0-l50.0 (recrystallized from isopropyl alcohol).

Analysis Calcd. for CnHmONCl Fmmd EXAMPLE 5'9 Z benzflphenfl yamma dimethylaminopropyl ether In the manner described in Example 57, by using. 2- benzyl gamma-bromopropyl ether and dimethylamine,

CHI

1 there is obtained Z-benzylphenyl gamma-dimethylaminopropyl ether (87% yield), ,B. P.

l49153/1 mm. Hydrochloride: M. P. 159-160.

Analysis:

Calcd. for CrsHnONCl F011 0 ---.-e-...' e-- 70.8 70. 6 H 1 7. 9 7. 8

EXAMPLE 2=befazylp1renyl beta-Jpyrralidylethyl ether CHr-CHI In the manner described in Example 57, by using 2-benzylphenyl beta-bromoet-hy-l ether and pyrrol-idine,

-there is obtained Z-benzylphenyl beta-l-pyrrolidylether (74% yield), B. P. 152'163/1 mm. Hydrochloride: M. P. 140.0-141.5 (recrystallized from acetone).

Analysis:

Calcd. for CnHuONCl Fmmd 72.1 72. 11 l 7. s V 7. z

'27 EXAMPLE 61 Z-benzylphenyl beta-1-(2-methylplperidyl)ethyl ether Calcd. for Ha 0 N 01 EXAMPLE 62 4-benzylphenyl gamma-di-n-butylaminopropyl ether CHaCHzCHzCH CHiCHzCHzCH:

In the manner described in Example 53, by using 4- benzylphenol and gamma-di-n-butylaminopropyl chloride hydrochloride, there is obtained 4-benzylphenyl gammadi-n-butylaminopropyl ether (75% yield), B. P. 197- 200/l mm. Hydrochloride: M. P. 960.098.0 (recrystallized from ethyl acetate).

28 EXAMPLE 54 2-(4-fluorobenzyl)phenyl beta-dimethylaminoethyl ether on,- F

In the manner described in Example 53, by using 2- (4'-fluorobenzyl)phenol, which may be prepared by reacting sodium phenoxide with 4-fiuorobenzyl chloride, and beta-dimethylaminoethyl chloride hydrochloride, there is obtained 2-(4-fluorobenzylphenyl beta-dimethylaminoethyl ether (72% yield), B. P. 140-146/2 mm. Hydrochloride: M. P. 131.0132.5 (recrystallized from isopropyl-Skellysolve B).

Analysis:

Calcd. for

EXAMPLE 65 4-fluoro-2-benzylphenyl beta-dimethylaminoethyl ether In, the manner described in Example 53, by using 4- fluoro-Z-benzylphenol, which may be prepared by reacting benzyl chloride with sodium 4-fluorophenoxide, and beta-dimethylaminoethyl chloride hydrochloride, there is obtained 4-fluoro-2-benzylphenyl beta-dimethylaminoethyl ether (89% yield), B. P. 131-134/1 mm. Hydrochloride: M. P. 124.5-125.5 (recrystallized from isopropyl alcohol-Skellysolve B). Analysis Analysis:

calcd' for Found Caled. for CnHuONCl CHHMONCIF Found EXAMPLE 63 EXAMPLE 66 4-chloro-2-benzylphenyl beta-diethylaminoethyl ether 4-bromo-2-benzylphenyl beta-dimethylaminoethyl ether CHr- CH:-

CaH; CHI

01- o-cmom-N Br 01H 60 on.

In like manner to Example 53, by using 4-chloro-2- benzylphenol and beta-diethylaminoethyl chloride hydrochloride, there is obtained 4-chloro-2-benzylphenyl beta-diethylaminoethyl ether, B. P. 175-188/l mm.

Analysis:

In the manner described in Example 53, by using 4- bromo-2-benzylphenol and beta-dimethylaminoethyl chloride hydrochloride, there is obtained 4-bromo-2- benzylphenyl beta-dimethylaminoethyl ether (89% yield), B. P. 164-l67/1.5 mm. Hydrochloride: M. P.

(recrystallized from isopropyl alcohol- Skellysolve B). f

Analysis:

Calcd. for O17H7iONBtCl mind 0 55. 1 55. 7 H 5. 7 5. 7 N. 3. s a. 8

EXAMPLE 67 4-iodo-2-benzylphenyl beta-dimethylaminoethyl ether 29 In the manner described in Example 53, by using 4- iodo-2-benzyl phenol, which may beprepared by reacting benzyl chloride with sodium 4-iodophenoxide, and betadimethylaminoethyl chloride hydrochloride, there is obtained 4-iodo-2-benzylphenyl beta-dimethylaminoethyl ether. Hydrochloride: M. P. 167.0170.0 (recrystallized from methyl isobutyl ketone).

Analysis:

Calcd. for

onmioNou Fmmd EXAMPLE 68 6-meth0xy-2-benzylphenyl beta-dimethylaminoethyl ether OH: OCH:

In the manner described in Example 53, by using 6- methoxy-Z-benzylphenol and beta-dimethylaminoethylchloride hydrochloride, there is obtained 6-methoxy-2- benzylphenyl beta-dimethylaminoethyl ether (83% yield), B. P. 144-l48/1 mm. Nitrate: M. P. 92.5-94.0 (recrystallized from isopropyl alcohol-Skellysolve B).

Analysis:

Caled. for Cu nOaM Found EXAMPLE 69 4-dimethylamino-2-benzylphenyl beta-dimethylamino- I ethyl ether In the manner described in Example 53, by using 4-dimethylamino-2benzylphenol, which may be prepared by reacting benzyl chloride with sodium 4-dimethylaminophenoxide, and beta-dimethylaminoethyl chloride hydrochloride, there is obtained 4-dimethylamino-2-benzylphenyl beta-dimethylaminoethyl ether 73% 'yield), B. P. 171-186/1 mm. Monohydrochloride: M. P. 154.0l56.0 (recrystallized from isopropyl alcohol).

Analysis:

In the manner described in Example 53, by using 2- (alpha-methylbenzyl)phenol, which may be prepared by reacting alpha-bromoethylbenzene with sodium phenoxide, and beta-dimethylaminoethyl chloride hydrochloride, there is obtained 2-(alpha-methylbenzyl)phenyl beta-dimethylaminoethyl ether (78% yield), B. 'P.

30 142-146/1 mm. Hydrochloride: M.P. l4l.0-142.5 (reggsltallized from-isopropyl alcohol- Skellysolve B).

ysrs:

Calcd. for CnHzrONCl Fmmd EXAMPLE 71 2-(3-thenyl)phenyl beta-dimethylaminoethyl ether In the manner described in Example 53, by using 2- (3'-thenyl)phenyl, which may be prepared by reacting 3-thenylbromide with sodium phenoxide, and beta-dimethylaminoethyl chloride hydrochloride, there is ob tained 2-(3-thenyl)pheny1 beta-dimethylaminoethyl ether (78% yield), B. P. 156-155 /2 mm. Dihydrogen citrate: M. P. 136.0-l37.5 (recrystallized from methanol-ether.)

To a solution of 6.5 grams 2-(2'-pyridylmethyl) phenol in ml. of toluene is added 1.5 grams of flake sodium hydroxide. The mixture is stirred and refluxed until the theoretical amount of water (0.6 ml.) has been caught in a Dean-Stark trap. A solution of beta-dimethylaminoethyl chloride in toluene is prepared by treating a toluene suspension of 10.7 grams of beta-dimethylaminoethyl chloride hydrochloride with an excess of 50% sodium hydroxide. The toluene solution is dried over anhydrous potassium carbonate, filtered and added dropwise to the above described solution of sodium 2-(2'-pyridylmethyl) phenoxide. The reaction mixture is then refluxed overnight. The mixture is cooled, extracted several times with water, and the toluene solution dried over potassium carbonate. Distillation gives 4.2 grams (46% yield) of 2 (2' pyridylmethy1)phenyl beta-dimethylaminoethyl ether, B. P. 159161 at less than 1 mm.

Analysis:

0alcd.for

CicHaiON: Found Hydrogen citrate: M. P. 149.0150.0 (dec.).

alysis:

Calcd. for

02H 0 5N7 Found 31 EXAMPLE 73 2-(2-furfuryl)phenyl beta-dimethylaminoeihyl ether CHI-U In the manner described in Example 53, by using 2-(2- furfuryl)phenol, which may be prepared by reacting 2- furfuryl bromide with sodium phenoxide, and beta-dimethylaminoethyl chloride hydrochloride, there is obtained 2-(2 furfuryl)phenyl beta dimethylaminoethyl ether.

EXAMPLE 74 7-benzyl-8-quinolyl beta-dimethylaminoethyl ether O-GHnCHz-N CH: N

In the manner described in Example 53, by using 7- benzyl-S-hydroxyquinoline, which may be prepared by reacting benzyl chloride with the sodium salt of 8- hydroxyquinoline, and beta-dimethylaminoethyl chloride hydrochloride, there is obtained 7-benzyl-8-quinolyl betadirnethylaminoethyl ether (86% yield), B. P. l90-197/l mm. Dihydrochloride. M. P. 205.0-207.0 (recrystah lized from methanol-ether).

Analysis:

01011 50132511 Found EXAMPLE 75 2- (Z-benzylphenoxymethyl) tetrahydropyrimidine Forty grams (0.15 mole) of ethyl 2-benzylphenoxyacetate, which may be prepared by reacting ethyl chloroacetate with sodium 2-benzylphenoxide according to the method disclosed in the copending application Serial Number 128,028, filed November 17, 1949, and 22.2 grams (0.3 mole) of 1,3-diamino-propane. are heated together on the steam bath for 48 hours. Distillation of the reaction mixture gives 26.4 grams (63% yield) of 2-(Z-benzylphenoxymethyl)tetrahydropyrimidine, B. P. 19 1-197 /25 mm. Hydrochloride: M. P. 176.5177.5 (recrystallized from isopropyl alcohol-ether).

Analysis:

Calcd. for O IBHZX ONzCl Fmmd 32 EXAMPLE 76 I-Allyl-Z-naphthyl beta-dimethylaminoethyl ether 0 11 -0 H=C H:

--CH2C Hr-N B. P. 139143/1 mm. Hydrochloride: M. P. 151.0- 152.5.

Analysis:

0 1 d.t' onfifzorihl mm EXAMPLE 77 2- (Z-benzylphenoxymethyl) -4 (5 -methylimidazoline /NCHOH1 O-OH2C/ N- H: H

Forty grams of ethyl 2-benzylphenoxyacetate and 39 grams of 1,2-propylenediamine are heated together for seven hours, distilling off alcohol and water as formed during this time. Distillation of the reaction mixture in vacuo gives 31.6 grams (75% yield) of 2-(2-benzyl- Beta-(o-benzylphenoxy)ethyl trimethylammonium iodide CH2- CE: /CHl I CH:

To a solution of 30 grams of N,N'-dimethyl-beta-(obenzylphenoxy)ethylarnine in 70 ml. of isopropyl alcohol is added, with cooling, 18.3 grams of methyl iodide. The solid which precipitates at once is collected by filtration and recrystallized from Water, giving 46.5 grams (99% yield) of beta-(o-benzylphenoxy)ethyl trimethylammonium iodide, M. P. 161.0162.0.

Analysis Calcd. for 01511140171 Fmmd 0 54. a 54. 1 H 6. 1 5. s

unease 33 31! EXAMPLE 79 ji. 4. EXAMPLE 82' Beta-(o-benzylphenoxy)ethyl ethyl dimethyldmmonium Betg (q-benzylphenoxy)ethyl trimethylammonium p- Y i; iodide t'oluen esulfonate CaHs OH! 7' OH: 6H:

.. +0Ht0H;'N O-GHaOHz-N mi 7. 7 m u CH3, W I C SO3-@CHg To a solution of 25.5-gr 'sof =N,N-dimethyl beta-(obenzyl-phenoxy)e'thyl amine in 100 ml. of isoprop l A solution of 12.7 grams of N,N-d1met.hyl beta-(oalcohol is added 20 grams of ethyl iodide. The following benzylphetwxw e y .amlne and 101 Of methyl day the crystalline product. filtered OE and recrystab ptoluene sulfonate m 300 ml. of acetone 1s allowed to lized from ethyl alcohol, giving 29.7 grams (72% yield) of beta (o benzylphenoxy)ethyl ethyl dimethylammonium iodide, M. P.156.5'158.0.

Analysis:

A i e;

. X MPLEsO I Bem-(o-benzylphenobcfiethyl dimeth l: bnzqhyvd'yb ammonium bromide CH3 CH1 A solution of 25.5 grams ao'f -N;N-dimethyl beta-(obenzylphenoxy) ethylamine-and 24.7 grams of benzohydryl bromide in 150 ml. of acetone is heated at reflux 1 for hours, then mostof the acetone is distilled off under reduced pressure. Ether is added to the residue, and crystallization is induced by coolingand scratching. The beta-(o-benzylphenoxy)ethyl dimethyl benzohydryl bromide thus obtained weights 45.2 grams (90% yield) and melts at 67.0,7 0.0 I V Manda-short time at room temperature, then diluted with ether. The oil which separates soon crystallizes, and is collected by filtration. There is obtained on recrystallization from ethyl acetate 19.8 grams (90% yield) of beta-(o-benzylphenoxy),ethyl trimethylammonium p-toluene'sulfonate, M. P. 70.0-80.0. The compound is very hygroscopic. I a I Analysis:

Found Analysis;

Analysis:

Oalcd. for

EXAMPLE 81 Beta (o benzylphenoxy)ethyl methylsulfate i 'isdlcrtt A solution of 12.7 grams at N,N-dimethyl beta-(obenzylphenoxy) ethylamin'e and 7.5 grams of dimethyltrimethylammonium sulphate in 50 ml. of acetone is allowed to stand for two days at room temperature, then; diluted with ether. The only quaternary crystallizes oncool mg, and 1s recrystallized, first from isopropyl alcohol, then from EXAMPLE s4 Beta-(o-benzylphenoxy)ethyl methyl diethylammonium' e zodtd CzHs acetone, to give 6.6 grams (35% yield) of beta-(0 75, is obtained in this manner 40.7 grams (96% yield) of benzylphenoxy)ethyl trimethylammonium methylsulfate, beta-(o-benzylphenoxy)ethyl methyl diethylarnmonium M. P. 93.0-98.0. The compound is very hygroscopic. iodide, P. 1385-1400.

Analysis: I Analys1s:

Olcd. I Cld.f I gti fl i N Found C2g2sO N I Found I 89.8.: I 59.3 0 56.5 56:4, 7.1 as H 6.6 6.8

spans:

35 EXAMPLE 85 Betiz-(o-benzyl-p-cresoaiy)ethyl trimethyldm hioriidm iodide I CH:

To a solution of 8.1 grams of N,N-dimethyl beta-(obenzyl-p-cresoxy)ethylamine in 30 ml. of isopropyl alcohol is added 4.8 grams of methyl iodide. The solution. becomes warm, and on cooling an oil separates, which slowly crystallizes. The solid is collected by filtration and recrystallized from methyl isobutyl ketone to give 10.5 grams (85% yield) of .beta-(o-benzyl-p-cresoxy)ethyl trimethylammonium iodide, M. P. 138.0-l42.0. 7

Analysis:

Caled. for C rvHnONI Found C 55. 55. 5 H G. 4 6. 5

EXAMPLE 86 Beta-(o-benzyl-p-etlioxyphenoxy)ethyl trimethylammonium iodide To a solution of 12.0 grams of N,N-dimethyl beta-(obenzyl-p-ethoxyphenoxy) ethylamine in 40 ml. of isopropyl alcohol is added 6.3 grams of methyl-iodide. Cooling and scratching induces crystallization. The solid is collected by filtration and recrystallized from methyl isobutyl ketone. There is obtained 10.5 grams-(60% yield) of beta-(o-benzyl-p-ethoxyphenoxy)ethyl trimethylammoninm iodide, M. P. 139.0-145.0.

Analysis:

Calcd. for C ioHrsOaNI Found EXAMPLE 8';

Beta-(o-benzyl-p-chlorophenoxy)ethyl lrimethylammonium iodide (JED-Q An aqueous solution of 6.2 grams of N,N-dimethyl beta-(o-benzyl-p-chlorophenoxy)ethylamine hydrochloride is made basic with sodium hydroxide and the liberated aminoether extracted into ether. The ether solution is dried over anhydrous potassium carbonate, filtered and the filtrate evaporated to dryness. The residual oil is taken up in 80 ml. of isopropyl alcohol and 3.1 grams of methyl iodide added thereto. Crystallization begins in a short time. The solid is filtered off and recrystallized from ethyl alcohol to give 6.8 grams (83% yield) of; beta-(o-benzyl-p-chlorophenoxy)ethyl trimethylarnmoni um iodide, M. P. 163.0164.0.

solution 'is added 9.4=grams of methyl iodide.

which slowly crystallizes.

plete, the solid is collected by filtration and recrystallized Beta-(o-benzyl-p-bromqphenoxy)eihyl trimethylammomum iodide To a solution of 10.6 grams of N,N-dimethyl beta-(obenzyl-p-bromophenoxy)ethylamine in 30 ml. of isopropyl alcohol is added 4.7 grams of methyl iodide. The solution'becomes warm, and on cooling, an oil separates,

When crystallization is comfrom isopropyl alcohol. There is obtained 13.6 grams yield) of beta-(o-benzyl-p-bromophenoxy)ethyl trimethylammonium iodide, M. P. 150.0-l53.0.

Analysis:

Calcd. for

CuHnONBrI Fmmd EXAMPLE 89 Beta- (o-benzyl-p-fluorophenoxy) ethyl frimethylammonium iodide To a solution of 5.5 grams of N,N-dimethyl beta-(obenzyl-p-fiuorophenoxy)ethylamine in 20 ml. of isopropyl alcohol is added 3.1 grams of methyl iodide. An exothermie reaction occurs, and an oil separates as the solution cools. The oil soon crystallizes and is filtered off. Recrystallization from dilute isopropyl alcohol gives 7.8 grams (94% yield) of beta-(o-benzyl-p-fiuorophenoxy)- ethyl trimethylammonium iodide, M. P. 198.0-200.0.

Analysis:

Calcd. for

CilHnONFI Fmmd EXAMPLE 90 Beta-(o- [p'-chlor0benzyl] phenoxy) ethyl trimethylammonium iodide i CH:

CHI

An aqueous solution of 17.5 grams of N,N-dimethy1 betao- [p-chlorobenzyl] phenoxy) ethylamine hydrochloride is made basic with sodium hydroxide and the liberated 'aminoether' extracted into ether. The ether solution is dried over anhydrous potassium carbonate, filtered and the filtrate evaporated to dryness. The residual oil is taken up in ml. 'of isopropyl alcohol and to this After a 51115;;rifiaekrystallizmionrs'bomplere, and the solid is areas 1 37' collected by filtration. Therejis obtained on recrystallizat on from ethyl alcohol 19.9 grams (86% yield) of beta-(o-[p'-ch1orobenzyl]phenoxy)ethyl trimethylammonium iodide, M. P. 163.0164.0.

Analysis:

Calcd. for cnnuoncu mm To a solution of 5.5 grams of N,N-dimethyl beta-(o- [p'-fluorobenzyl]phenoxy)ethylamine in ml. of isoacetone-isopropyl alcohol. There is obtained 10.0 grams (42% yield) of beta-(o-benzyl-p-chloro-phe noxy)ethyl propyl alcohol is added 3.1 grams of methyl iodide. An

exothermic reaction occurs, and as the. reaction ,mixture cools, an oil separates. This oil slowly'crystallizes,and the solid is collected by filtration. It is recrystallized from dilute isopropyl alcohol, giving 7.9, grams; (95% yield) of beta-(o-[p'-fluorobenzyl]phenoxy)ethyl tri-. methylammonium iodide, M. P. 15 5.5-157.0

EXAMPLE 94 Gamma-(o-benzylphenoxy) -beta,beta-dimethylpropyl trimethylammonium iodide OH: I CHs I To a solution of 11.9 grams of N,N-dimethyl gamma- (o-benzylphenoxy)-beta,beta-dimethylpropylamine in 60 ml. of isopropyl alcohol and 5 ml. of Water is added 11.4 grams of methyl iodide. The solution is heated to boiling, cooled and diluted with ether. After standing one day at room temperature, the solid is collected by filtration. Recrystallization of the solid from isopropyl alcohol gives 12.3 grams (70% yield) of gamma- (o-benzylphenoxy) -beta,beta-dimethylpropyl trimethylammonium iodide, M. P. 171.5-172.5.

CHI

Analysis: j Analysis:

. 7 05' I FM EXAMPLE 92 EXAMPLE 95 Beta-(0-benzyl-p-chl0r0phenoxy)ethyl methyl diethyl- Gamma-(o-benzylphenoxy)pr0pyl trimethy'lammonium ammonium iodide 5* iodide CH2- QH, I 01H. one. i I on. on, CI- O CHzOHz N o-cmomcm-N I I/\ \CH' I CH:

To a solution of 15.8 grams of N,N-diethyl.beta-(obenzyl-p-chlorophenoxy)ethylamine in. ml. ,of visopropyl alcohol is added 10.0 gra'rnsjof methyliodide.

The solution is heated to reflux, filtered and allowedto cool. The precipitated solid is collected by filtration and; recrystallized from isopropyl alcohol, giving 18.4 grams (80% yield) of beta (o-benzyl-pchlormphenoxy)ethyl methyl diethyl ammonium iodide, M. P. l 49.0-' .150'.5.

Analysis:

Calcd.ior CWHIIONOII Fmm'i EXAMPLE 93 Beta-(o-benzyl-p-chlorophenoxy)ethyl triethylammonium iodide -Q An aqueous solution of 13.0 grams of N,N-dimethyl gamma-(o-benzylphenoxy)propylamine hydrochloride is made basic with sodium hydroxide and the liberated aminoether extracted into ether. The ether solution is dried over anhydrous potassium carbonate, filtered, and the filtrate evaporated to dryness. The residual oil is dissolved in ml. of isopropyl alcohol and to this solution is added 6.6 grams of methyl iodide. The solid quaternary precipitates from the cooled solution in a short time and is collected by filtration. Recrystallization from the water gives 16.1 grams (92% yield) of gamma-(o-benzylphenoxy)propyl trimethylammonium iodide hemihydrate, M. P. 186.0187.0.'

Analysis:

Calcd. for

CioHieONLiHaO 9 EXAMPLE 96 An aqueous solution of 44.7 grams of N,N-dimethyl beta-(p-benzylphenoxy)ethylamine dihydrogen citrate is EXAMPLE 99 Betd (dbenzyl-P-Chlorophenoxy)ethyl dimethyl n-octadecylammonium bromide v A solution of 7.2 grams of N,N-dimethyl beta-(obenzyl-p-chlorophenoxy)ethylamine and 10.0 grams of n-octadecyl bromide in ml. of isopropyl alcohol is refluxed for 24 hours. Evaporation of the solvent leaves the desired beta-(o-benzyl-p-chlorophenoxy)ethyl dimethyl n-octadecylammonium bromide as a viscous yellow oil which crystallizes on standing.

EXAMPLE 100 Beta-(0-benzyl-p-chlorophenoxy)ethyl dimethyl octylphenoxyethoxyethylammonium chloride CH: CH;

EXAMPLE 97 Betao-2-thenylphenoxy ethyl trimethylammonium iodide I CH3 To a chilled solution of 26.1 grams of N,N-dimethyl beta-(o-2-thenylphenoxy)ethylamine in 150 ml. of isopropyl alcohol is added 15.6 grams of methyl iodide. The solid which precipitates almost at once is collected by filtration and recrystallized from methyl alcohol. There is obtained in this manner 30.4 grams (75% yield) of beta-(o-2-thenylphenoxy)ethyl trimethylammonium iodide, M. P. 182.0-183.0.

Analysis:

02%??i3is Found EXAMPLE 98 Beta- (0-benzyl-p-chlorophenoxy ethyl d 1' methyl n-octylammonium bromide A solution of 7.2 grams of N,N-dimethyl beta-(obenzyl-p-chlorophenoxy)ethylamine and 5.8 grams of noctyl bromide in 25 ml. of isopropanol is refluxed for 32 hours. Evaporation of the solvent leaves the desired beta-(o-benzyl-p-chlorophenoxy)ethyl dimethyl n-octylammonium bromide as a viscous yellow oil, which crystallizes on trituration with ether. Recrystallization from ethyl acetate-ether gives 10.3 g. of crystalline material, M. P. 122.0-123.0

Analysis:

Found Calcd. for |Cg Hz7ONBrCl CH: CH:

A solution of 7.2 grams of N,N-dimethyl beta-(obenzyl-p-chlorophenoxy)ethylamine and 9.4 grams of octylphenoxyethoxyethyl chloride in 25 ml. of isopropanol is refluxed for 40 hours. Evaporation of the solvent leaves the desired beta-(o-benzyl-p-chlorophenoxy)ethyl dimethyl octylphenoxycthoxyethyl ammonium chloride as a viscous light yellow oil.

EXAMPLE 101 Cetyl dimethyl beta-(o-thenylp'henoxy)ethylammonium bromide CHI-\S u A mixture of 25.0 grams of N,N-dimethyl beta-(olhenylphenoxy) ethylamine, 50 grams of cetyl bromide and 25 ml. of benzyl alcohol is heated on the steam bath for 20 hours. Excess halide and solvent are then distilled off at} mm. pressure by means of a bath heated to 210, 28 ml. of distillate being collected. The yellow, viscous, oilyproduct is soluble in ether and acetone and only slightly soluble in water. This product shows strong germicidal activity.

EXAMPLE 102 Beta-(b-benzylphenoxy)ethyl dimethyl n-octadecylammonium bromide A mixture of 5.4 :grams of N,N-dimethyl beta-(obenzylphenoxy) ethylamine, 7.0 grams of octadecyl .bromide and 25' ml. of methanol is refluxed on the steambath for' six days- Methanol is removed on the steambath in a current of air. The residual viscous yellow oil, which'is soluble in acetone, ether, and alcohol is only slightly 'soluble' in water. It crystallized from dilute 5: acetone j-orlwater. Thissalt is useful as a germicide. 

1. A NEW CLASS OF COMPOUNDS CONSISTING OF THE FREE BASE, ITS ACID ADDITION SALTS AND ITS QUATERNARY SALTS, SAID FREE BASE HAVING THE GENERAL FORMULA 